The present invention relates to the field of piperidinyloxy, pyrrolidinyloxy and azetidinyloxy oxazolidinone compounds having antibacterial activity, pharmaceutical compositions containing the compounds, and methods of treating bacterial infections with the compounds.
Oxazolidinones have been identified, within the last twenty years, as a new class of antibacterials which are active against numerous multidrug-resistant gram positive organisms. Particularly problematic pathogens include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin- and cephalosporin-resistant Streptococcus pneumoniae. As a class oxazolidinones exhibit a unique mechanism of action. Studies have shown that these compounds selectively bind to the 50S ribosomal subunit and inhibit bacterial translation at the initiation phase of protein synthesis. Exemplary members of oxazolidinones are linezolid (see WO 95/07271) and eperezolid. 
The following references relate to various oxazolidinone type compounds disclosed as having antibacterial activity:
U.S. Pat. No. 4,705,799 to W. A. Gregory discloses aminomethyl oxooxazolidinyl benzene derivatives, including the sulfides, sulfoxides, sulfones and sulfonamides, such as (1)-N-[3-[4-(methylsulfinyl)-phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.
U.S. Pat. No. 5,565,571 to Barbachyn et al. discloses substituted aryl- and heteroarylphenyloxazolidinones.
U.S. Pat. No. 5,792,765 to Riedl et al. relates to new substituted oxazolidinones.
U.S. Pat. No. 5,910,504 to Hutchinson discloses phenyloxazolidinone compounds having a nitrogen containing hetero-aromatic ring substitution attached through one of the nitrogen atoms.
WO 93/09103 (Barbachyn et al.) discloses substituted aryl- and heteroarylphenyloxazolidinones.
WO 95/07271 (Barbachyn et al.) discloses oxazine and thiazine oxazolidinone derivatives.
WO 98/54161 (Hester et al.) provides oxazolidinone antibacterial agents having a thiocarbonyl functionality.
The invention provides new piperidinyloxy, pyrrolidinyloxy and azetidinyloxy compounds of Formula I 
wherein
(a) R3 is selected from H, alkyl, xe2x80x94COR4, xe2x80x94(CH2)theteroaryl, xe2x80x94CHR5R6, xe2x80x94(CH2)taryl, xe2x80x94SO2NR5R6, and xe2x80x94SO2R9;
(b) R4 is selected from H, xe2x80x94OR5, alkyl, alkylaryl, xe2x80x94(CH2)aryl, xe2x80x94(CH2)theteroaryl, xe2x80x94(CH2)tOR5, xe2x80x94(CH2)tNR7R8, xe2x80x94CHR5R6, and xe2x80x94NR5R6 optionally forming a cyclic amino derivative;
(c) R5 and R6 are independently selected from H, alkyl, alkylaryl, haloaryl, xe2x80x94(CH2)taryl, xe2x80x94(CH2)theteroaryl, and acyl;
(d) R7 and R8 are independently selected from H, alkyl, xe2x80x94COR9, xe2x80x94SO2R9 and xe2x80x94CO2R9; and
(e) R9 is selected from H, alkyl, aryl and alkylaryl;
R2 is selected from C(O)R9, C(O)OR9, 
xe2x80x83R2ais H or acyl with the proviso that when R3 is selected from alkyl, xe2x80x94(CH2)taryl, xe2x80x94(CH2)theteroaryl, and xe2x80x94CHR5R6, R2ais H;
X is N or CH;
Y is selected from H, halogen, alkoxy, and alkyl; and
t is an integer of 0 to 4;
or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof.
Compounds of the above formula are useful as antibacterial agents for the treatment of bacterial infections in a subject such as human and animal.
The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of the compound of Formula I.
The present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective amount of the compound of Formula I.
Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.
Relative to the above description, certain definitions apply as follows.
Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
Unless specified otherwise, the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, and xe2x80x9calkynyl,xe2x80x9d whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number within this range. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. xe2x80x9cAlkoxyxe2x80x9d radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. xe2x80x9cCycloalkylxe2x80x9d groups contain 3 to 8 ring carbons and preferably 5 to 7 ring carbons. The alkyl group and alkoxy group may be independently substituted with one or more members of the group including, but not limited to, mono-, di-, tri-, or per-halogen, alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, amino, substituted amino, OH, CN, mercapto, nitro, and C1-8 acyloxy.
The term xe2x80x9cacylxe2x80x9d as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group.
The term xe2x80x9cAcxe2x80x9d as used herein means acetyl.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo and iodo. (Mono-di-, tri-, and per-)halo-alkyl is an alkyl radical substituted by independent replacement of the hydrogen atoms thereon with halogen.
xe2x80x9cArylxe2x80x9d or xe2x80x9cAr,xe2x80x9d whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, xe2x80x94OH, xe2x80x94CN, mercapto, nitro, amino, substituted amino, alkyl, xe2x80x94O-alkyl, xe2x80x94S-alkyl, xe2x80x94NH-alkyl, xe2x80x94N(alkyl)2, (mono-, di-, tri-, and per-)halo-alkyl, formyl, xe2x80x94COR5, xe2x80x94COOR5, xe2x80x94CONHR5, xe2x80x94CONR5R6, xe2x80x94SOR5, xe2x80x94SO2R5, xe2x80x94SO2NHR5, xe2x80x94SO2NR5R6, alkyl-COO, alkyl-CONHR5, or carboxamide or a second aryl ring, wherein R5 and R6 are defined as hereinabove. Illustrative aryl radicals include, for example, phenyl, naphthyl, diphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. xe2x80x9cPhxe2x80x9d or xe2x80x9cPHxe2x80x9d denotes phenyl.
Whenever the term xe2x80x9calkylxe2x80x9d, xe2x80x9cacylxe2x80x9d, or xe2x80x9carylxe2x80x9d or either of their prefix roots appear in a name of a substituent (e.g., aralkyl, dialkylamino) it shall be interpreted as including those limitations given above for xe2x80x9calkylxe2x80x9d, xe2x80x9cacylxe2x80x9d, and xe2x80x9caryl.xe2x80x9d Designated numbers of carbon atoms (e.g., C1-8) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
Whether used alone or as part of a substituent group, xe2x80x9cheteroarylxe2x80x9d refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical being joined to the rest of the molecule via any of the ring atoms, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, and the like. The heteroaryl group may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, xe2x80x94OH, xe2x80x94CN mercapto, nitro, amino, substituted amino, alkyl, xe2x80x94O-alkyl, xe2x80x94S-alkyl, xe2x80x94NH-alkyl, xe2x80x94N(alkyl)2, (mono-, di-, tri-, and per-)halo-alkyl, formyl, xe2x80x94COR5, xe2x80x94COOR5, xe2x80x94CONHR5, xe2x80x94CONR5R6, xe2x80x94SOR5, xe2x80x94SO2RS, xe2x80x94SO2NHR5, xe2x80x94SO2NR5R6, alkyl-COO, alkyl-CONH, or carboxamide, wherein R5 and R6 are defined as hereinabove. Heteroaryl may also be substituted with a mono-oxo to give 4-oxo-1H-quinoline and the like.
A xe2x80x9ccyclic aminoxe2x80x9d derivative is a 4 to 8 membered nitrogen containing cyclic group where the other remaining members are selected from carbon, nitrogen, oxygen or sulfur, for instance an azetidinyl group, pyrrolidinyl group, piperidinyl group, morpholino group, piperazinyl, or groups of the following formulae: 
wherein p is xe2x88x922 to 4 and q is 1-4.
xe2x80x9cHeterocyclylxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d is a 3- to 8-member saturatedor partially saturated single or fused ring system which consists of carbon atoms and from one to three heteroatoms selected from N, O and S. The heterocyclyl group may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure. Examples of heterocyclyl groups include, but are not limited to pyridine, pyrimidine, oxazoline, pyrrole, imidazole, morpholine, furan, indole, benzofuran, pyrazole, pyrrolidine, piperidine, and benzimidazole. xe2x80x9cHeterocyclylxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d may be substituted with one or more independent groups including, but not limited to, H, halogen, oxo, OH, alkyl, substituted alkyl, amino, substituted amino, carboxyl, alkylcarboxyl, and alkoxy.
Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
The compounds of the instant invention are asymmetric in the oxazolidinone ring at the 5-position and thus exist as optical antipodes. As such, all possible optical antipodes, enantiomers or diastereomers resulting from additional asymmetric centers that may exist in optical antipodes, racemates and Aft racemic mixtures thereof are also part of this invention. The antipodes can be separated by methods known to those skilled in the art such as, for example, fractional recrystallization of diastereomeric salts of enantiomerically pure acids. Alternatively, the antipodes can be separated by chromatography on a Pirkle column.
The phrase xe2x80x9ca pharmaceutically acceptable saltxe2x80x9d denotes salts of the free base which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. These salts may be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, methyl sulfonic acid, salicyclic acid and the like. Suitable salts are furthermore those of inorganic or organic bases, such as KOH, NaOH, Ca(OH)2, Al(OH)3, piperidine, morpholine, ethylamine, triethylamine and the like.
Also included within the scope of the invention are the hydrated forms of the compounds which contain various amounts of water, for instance, the hydrate, hemihydrate and sesquihydrate forms.
The term xe2x80x9csubjectxe2x80x9d includes, without limitation, any animal or artificially modified animal. As a particular embodiment, the subject is a human.
The term xe2x80x9cdrug-resistantxe2x80x9d or xe2x80x9cdrug-resistancexe2x80x9d refers to the characteristics of a microbe to survive in presence of a currently available antimicrobial agent such as an antibiotic at its routine, effective concentration.
The compounds described in the present invention possess antibacterial activity due to their novel structure, and are useful as antibacterial agents for the treatment of bacterial infections in humans and animals.
In particular, compounds of Formula I wherein X is CH are embodiments of the present invention for such purposes.
Compounds of Formula I wherein R2 is C(O)R9 wherein R9 is as described above are particular embodiments of this invention.
More particularly, compounds of Formula I wherein R9 is H or alkyl are also embodiments of this invention.
Compounds of Formula I wherein R1
wherein R3is as described above are further particular embodiments of this invention.
More particularly, compounds of Formula I wherein R2ais H and R3 is selected from xe2x80x94COR4, xe2x80x94SO2R9 and (CH2)theteroaryl wherein R4, R9 and t are as described above are embodiments of this invention.
Still more particularly, compounds of Formula I wherein R4 is selected from OR5, xe2x80x94(CH2)tOR5, alkyl, xe2x80x94(CH2)taryl, and xe2x80x94(CH2)theteroaryl wherein R5 and t are as described above are embodiments of this invention.
The following are yet other particular embodiments of the present invention for such purposes:
(S)-N-[[3-[3-fluoro-4-{N-(benzyloxyacetyl)piperidinyl-4-oxy}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-{N-(xcex1-hydroxyacetyl)piperidinyl-4-oxy}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-{N-(methanesulfonyl)piperidinyl-4-oxy}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-{N-(methoxycarbonyl)piperidinyl-4-oxy}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-{N-(2-pyrimidinyl)piperidinyl-4-oxy}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-{N-(3-cyanobenzoyl)piperidinyl-4-oxy}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-{N-(5-cyano-2-pyridyl)piperidinyl-4-oxy}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-{N-(2-thienylcarbonyl)piperidinyl-4-oxy}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-{N-(xcex1-hyd roxyacetyl)piperidinyl-3-oxy}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; and
(S)-N-[[3-[3-Fluoro-4-{N-(benzyloxyacetyl)pyrrolidinyl-3-oxy}phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
Finally, this invention provides a process for preparing a compound of Formula Ia 
wherein R1 is a moiety of the formula: 
wherein:
R is selected from Boc, xe2x80x94CH(Ph)2 or xe2x80x94COCH2OCH2Ph, n is 0, 1 or 2, m is 0 or 1, and R2, X, and Y are as described above, which process comprises:
(a) reacting a compound of Formula a with a compound of Formula axe2x80x2 or axe2x80x3 to form a compound of Formula b; 
(b) converting the compound of Formula b to a compound of Formula d;
(c) reacting the compound of Formula d with 
to form a compound of Formula e; 
(d) converting the compound of Formula e to a compound of Formula f;
(e) converting the compound of Formula f to a compound of Formula g; 
(f) converting the compound of Formula g to a compound of Formula p; and
(g) converting the compound of Formula p to a compound of Formula Ia.
The compounds of Formula I may be prepared from readily available starting materials such as known oxazolidinone intermediates in accordance with synthetic methods well known in the art. The following are representative procedures outlined in Schemes I and II: 
In accordance with Scheme I, wherein R is Boc, xe2x80x94CH(Ph)2or xe2x80x94COCH2OCH2Ph, R11 is xe2x80x94COR9 or xe2x80x94CO2R9, Rxe2x80x2 is any of the substituents on an aryl or heteroaryl group as described above, Rxe2x80x3 is selected from R9 and xe2x80x94NR5R6, Rxe2x80x2xe2x80x3 is selected from alkyl, substituted alkyl and xe2x80x94CHR5R6, R2axe2x80x2 is optionally substituted alkyl, Rxe2x80x3xe2x80x3 is xe2x80x94SCH3 or xe2x80x94OCH3, R10 is xe2x80x94NR9R9, R9, xe2x80x94SR9, or xe2x80x94NHR9, n is 0, 1 or 2 and m is 0 or 1, and X, Y, R4, R5, R6, R9, and t are as described above, an appropriately substituted halo-nitrobenzene such as that of Formula axe2x80x2 or an appropriately substituted halo-nitropyridine such as that of Formula axe2x80x3 is added to a compound of Formula a (all of which are either commercially available or may be readily prepared by known methods) in acetone, dimethylformamide (DMF), or tetrahydrofuran (THF). The mixture is treated with an appropriate base such as potassium t-butoxide (KOtBu) to obtain the corresponding compound of Formula b. The compound of Formula b may be reduced to the corresponding compound of Formula c under appropriate conditions such as H2, Pd/C and ethanol (EtOH) or NH4OCOH, Pd/C and methanol (MeOH). Then compound c is treated with benzylchloroformate (CbzCl) in the presence of an appropriate base such as cesium carbonate (CsCO3) in an appropriate solvent such as THF, H2O or acetone to obtain the corresponding compound of Formula d. Compound d is then treated with an appropriate base such as nBuLi, followed by addition of glycidyl butyrate in an appropriate solvent such as THF to obtain the corresponding compound of Formula e. The compound of Formula e is treated with methanesulfonyl chloride (MsCl) and an appropriate base such as triethylamine (NEt3) in an appropriate solvent such as methylene chloride (CH2Cl2). After standard workup, sodium azide (NaN3) is then added into the mixture in an appropriate solvent such as dimethylformamide (DMF) and heated at a preferred temperature range of 70xc2x0 C. to 90xc2x0 C. to obtain the corresponding compound of Formula f. The compound of Formula f may be reduced under appropriate conditions such as H2 and Pd/C in an appropriate solvent such as ethyl acetate (EtOAc), or the compound of Formula f may be reduced using triphenylphosphine (PPh3) and THF/H2O to obtain the corresponding compound of Formula g.
The compound of Formula g can be treated with an appropriate acylating agent such as acetic anhydride (AC2O) or acetyl chloride (AcCl), along with an appropriate base such as pyridine or NEt3 to give the corresponding compound of Formula h. The compound of Formula g can also be treated with an appropriate imidate to give the corresponding compound of Formula i. Compound h wherein R is xe2x80x94CH(Ph)2 can be converted to the corresponding compound of Formula w by reacting with R2axe2x80x2C(O)Cl in the presence of a base such as TEA. Compounds j and k can be obtained from compounds h and i, respectively, by deprotection with either trifluoroacetic acid (TFA) in an appropriate solvent such as CH2Cl2 or with Pd/C in an appropriate solvent such as EtOH or EtOAc.
Compounds of Formulae o, q, r, s, and u may be obtained in accordance with different routes as shown in Scheme II: 
The compound of Formula j or k can be treated with an appropriate alkylating agent represented by CIRxe2x80x2xe2x80x3 in the presence of an appropriate base such as NEt3 in an appropriate solvent such as CH2Cl2 or THF to obtain the corresponding compound of Formula u. Alternatively, the compound of Formula j or k can be treated with an appropriate sulfonyl chloride represented by Rxe2x80x3SO2Cl such as MsCl in the presence of an appropriate base such as NEt3 in an appropriate solvent such as CH2Cl2 or THF to obtain the corresponding compound of Formula r. Still alternatively, the compound of Formula j or k can be treated with an appropriate alkylating agent represented by 
wherein Z1 and Z2 are independently N or CH, in the presence of an appropriate base such as NEt3 in an appropriate solvent such as CH2Cl2 or THF to obtain the corresponding compound of Formula q. In addition, the compound of Formula j or k can also be treated with an appropriate acylating agent represented by R4COCl such as AcCl in the presence of an appropriate base such as NEt3 in an appropriate solvent such as CH2Cl2 or THF to obtain the corresponding compound of Formula o. In several cases, R4 contains a protected amine or protected alcohols moiety. After removal of the protecting group, the resulting amine or alcohol can be further derivatized. Compounds of Formulae o and r can be converted to compounds of Formulae v and s, respectively, by reacting with R2axe2x80x2C(O)Cl in the presence of a base such as TEA.
These compounds have antimicrobial activity against susceptible and drug resistant S. aureus, S. epidermidis, S. pneumoniae, E. faecalis, E. faecium, Moraxella catarrhalis and H. influenzae. These compounds are particularly useful against drug resistant Gram positive cocci such as methicillin-resistant staphylococci and vancomycin-resistant enterococci. These compounds are useful in the treatment of community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital-acquired lung infections, bone and joint infections, and other bacterial infections.
Minimal inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art. The in vitro antimicrobial activity of the compounds was determined by the microdilution broth method following the test method from the National Committee for Laboratory Standards (NCCLS). This method is described in the NCCLS Document M7-A4, Vol. 17, No. 2, xe2x80x9cMethods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobicallyxe2x80x94Fourth Editionxe2x80x9d, which is incorporated herein by reference.
In this method two-fold serial dilutions of drug in cation adjusted Mueller-Hinton broth are added to wells in microdilution trays. The test organisms are prepared by adjusting the turbidity of actively growing broth cultures so that the final concentration of test organism after it is added to the wells is approximately 5xc3x97104 CFU/well.
Following inoculation of the microdilution trays, the trays are incubated at 35xc2x0 C. for 16-20 hours and then read. The MIC is the lowest concentration of test is compound that completely inhibits growth of the test organism. The amount of growth in the wells containing the test compound is compared with the amount of growth in the growth-control wells (no test compound) used in each tray. As set forth in Table 1, compounds of the present invention were tested against a variety of Gram positive and Gram negative pathogenic bacteria resulting in a range of activities, from 1 to xe2x89xa7128 xcexcg/mL depending on the organism tested.
This invention further provides a method of treating bacterial infections, or enhancing or potentiating the activity of other antibacterial agents, in warm-blooded animals, which comprises administering to the animals a compound of the invention alone or in admixture with another antibacterial agent in the form of a medicament according to the invention.
When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, diluents, and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing for example, from about 0.5% to 5% of suspending agent, syrups containing, for example, from about 10% to 50% of sugar, and elixirs containing, for example, from about 20% to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5% to 5% suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.
Compositions for topical application may take the form of liquids, creams or gels, containing a therapeutically effective concentration of a compound of the invention admixed with a dermatologically acceptable carrier.
In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred. These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacological acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.1 mg/kg to about 400 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 0.07 g to 7.0 g, preferably from about 100 mg to 1000 mg. Dosage forms suitable for internal use comprise from about 100 mg to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
The production of the above-mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredients(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).